Genital tract infection with Neisseria gonorrhoeae (gonorrhea) does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency, and resistance even to the latest generations of antibiotics continues to emerge. There is no vaccine available, and none appears to be on the horizon of development. It has recently been demonstrated that N. gonorrhoeae subverts the immune system for its own benefit by eliciting innate responses that it can survive and by suppressing specific adaptive responses that would eliminate it. However, this induced immunosuppression can be reversed by intravaginal treatment with the cytokine interleukin-12 encapsulated in sustained release microspheres (IL-12/ms), a proprietary product developed by TherapyX, Inc., to elicit effective immune responses against existing infection with N. gonorrhoeae and thereby promote therapeutic clearance of the infection. In this SBIR application, a novel experimental gonococcal vaccine will be evaluated in a mouse model of vaginal gonococcal infection that is accepted as the only currently available animal model. Phase I aims to establish Proof-of-Principle that a vaccine consisting of gonococcal outer- membrane vesicles plus IL-12/ms given intravaginally can induce protective immunity against genital gonococcal infection, and generate recallable T-cell and antibody responses to N. gonorrhoeae. The duration of immunity, and protection against different strains of N. gonorrhoeae, will be determined. Successful completion of Phase I will lead to Phase II in which the vaccine components, dosage, and immunization regimen will be optimized, cross-protection and long-term efficacy against a diversity of naturally occurring strains of N. gonorrhoeae, and toxicity will be evaluated in preparation for clinical trial.